1. Field of the Invention
The present invention relates to a method for obtaining optically active anhydrous phenylalanine crystals which are useful as a pharmaceutical starting powder, a pharmaceutical intermediate and a starting material of a sweetener.
2. Prior Art
L-phenylalanine is an essential amino acid which is nutritionally indispensable, and is industrially useful as a starting material in the preparation of L-aspartyl-L-phenylalanine methyl ester, which is a sweetener.
Optionally active phenylalanine is conventionally obtained by (a) separation from a hydrolyzate of a protein such as defatted soybean, (b) by fermentation or (c) by direct synthesis. In these methods, crystallization and precipitation of the optically active phenylalanine are generally carried out to purify it. When the optically active phenylalanine-containing solution is crystallized and precipitated at a pH in the range of from 3 to 9, either anhydrous crystals (hereafter referred to as ".alpha.-form crystals") or monohydrate crystals (hereafter referred to as ".beta.-form crystals") of the optically active phenylalanine are obtained. The .alpha.-form crystals are plate or flake crystals, while the .beta.-form crystals are fine needle crystals. Further, the .alpha.-form crystals exhibit good separability from the mother liquor, and show less entrainment of the mother liquor. Therefore, .alpha.-form crystals are industrially preferred over .beta.-form crystals. Thus, methods of obtaining high-quality .alpha.-form crystals stably have been extensively studied.
The following methods have been previously used to obtain high-quality .alpha.-form crystals:
(1) Japanese Laid Open Patent Application (Kokai) No. 91,062/1992 discloses a method in which sodium chloride in an amount of at least 20 g/100 g.H.sub.2 O is added to a phenylalanine-containing aqueous solution, and the mixture is cooled to 30.degree. C. or lower to crystallize and precipitate phenylalanine.
(2) Japanese Laid-Open Patent Application (Kokai) No. 103,565/1992 discloses a method in which a surfactant such as a sorbitan alkyl ester or polyoxyethylenesorbitan alkyl ester is added to an aqueous solution containing phenylalanine and ammonium chloride to crystallize and precipitate phenylalanine.
(3) Japanese Laid-Open Patent Application (Kokai) No. 304,971/1993 discloses a method in which, when the concentration of phenylalanine in the phenylalanine fermentation liquid is above the solubility during cultivation, .alpha.-form seed crystals are added to crystallize and precipitate phenylalanine.
Further, the following methods have been previously used to obtain phenylalanine in high yield:
(4) Japanese Laid Open Patent Application (Kokai) No. 163,215/1993 discloses a method of isolating phenylalanine in which from 20 to 40% by weight of ammonium sulfate are added to a phenylalanine-containing aqueous solution, and the mixture is filtered at a temperature of 30.degree. C. or lower.
(5) Japanese Laid-Open Patent Application (Kokai) No. 178,801/1993 discloses a method of crystallizing and precipitating phenylalanine in which at least 8% by weight of ammonium sulfate are added to a phenylalanine aqueous solution obtained by an enzymatic reaction of cinnamic acid and ammonia.
However, these methods have not been studied for obtaining the .alpha.-form crystals stably. Even if the .alpha.-form crystals are formed, only the concentration of each additive in the crystallizing solution has been defined. Systematic considerations have not been offered.